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John K. Baker - One of the best experts on this subject based on the ideXlab platform.

  • identification of the glucuronides of the hydroxylated metabolites of the antimalarial Arteether in rat plasma and urine by thermospray high performance liquid chromatography mass spectrometry
    Journal of Pharmaceutical Sciences, 1997
    Co-Authors: Kumar Ramu, John K. Baker
    Abstract:

    A method was developed to quantitate the glucuronide conjugates (phase II metabolites, log P = 0.6-1.8) of the phase I hydroxylated metabolites (log P = 2.6-2.7) of beta-Arteether (2) (log P = approximately 4.0) in rat plasma and urine. The biological fluids were extracted with a C-18 solid-phase cartridge, then subjected to analysis by thermospray high-performance liquid chromatography/mass spectroscopy with a C-18 reversed-phase analytical column in the selected ion monitoring mode. The detection limits for these glucuronide conjugates in plasma and urine ranged from 25 to 60 ng/mL, and the detection limits were appropriate for the biological activity of these glucuronide conjugates in plasma. Following intravenous administration of Arteether (11.6 mg/kg), the formation of these glucuronide conjugates in rat urine was undetected (below detection limit) over 24 h. However, in rat plasma, formation of 9alpha-hydroxyArteether glucuronide (13; 255 ng/mL, IC50 = 6560 ng/mL, log P = 0.93) was noted at 15 min post-injection. Although several of the glucuronide metabolites of Arteether retained sufficient in vitro antimalarial activity to be potentially useful antimalarial agents if administered as prodrugs, the levels of the glucuronides formed from Arteether were too low to contribute to the antimalarial activity observed for the parent compound.

  • synthesis characterization and antimalarial activity of the glucuronides of the hydroxylated metabolites of Arteether
    Journal of Medicinal Chemistry, 1995
    Co-Authors: Kumar Ramu, John K. Baker
    Abstract:

    The hydroxylated metabolites (log P 2.6-2.7) of beta-Arteether (1) in rat liver microsomes that retain their endoperoxide moiety showed comparable in vitro antimalarial activity to that of the parent drug Arteether (log P = 3.89). The search for analogs of artemisinin (7) more suitable for intravenous use led to the synthesis of the glucuronide conjugates of the phase I hydroxylated metabolites of Arteether which were found to have good water solubility, yet retained moderate lipophilicity (log P = 0.6-1.8). While a strong correlation was observed between the log P value of the glucuronides, the phase I metabolites, and the parent compound, it was found that 9 beta-hydroxyArteetherglucuronide (26) was the most active and the most polar (log P = 0.61) of the glucuronides. While the in vitro antimalarial activity of 26 (IC50 = 89.3 ng/mL) was found to be much less than that for the parent compound, the activity of 26 was within a range that would have potential therapeutic use.

  • novel rearrangements of the trioxane ring system of the antimalarial Arteether upon treatment with acid in an aqueous methanol solvent system
    Heterocycles, 1994
    Co-Authors: John K. Baker, Hsien Tao Chi
    Abstract:

    While Arteether does not have a uv-chromophore, the treatment of Arteether with a HCl, water, methanol system has been previously proposed as a method of generating a uv-chromophore upon which to base a quantitative analysis. The present study demonstrates that the originally proposed structure for the product was not correct and that the reaction is far more complex than originally proposed. It was found that the reaction yields 5 different α,β-unsaturated ketones (A-1, A-2, A-3, A-4, and A-5; whoses structures are reported here for the first time) that have strong uv chromophores and 4 additional products (new compounds B-1 and B-2; previously reported α-artemether and βartemether) that do not have any significant chromophores. The structure and stereochemistry of these novel reaction products were determined using thermospray hplc/ms, 1 H-nmr, 13 C-nmr, and two-dimensional nmr methods

  • Decomposition of Arteether in Simulated Stomach Acid Yielding Compounds Retaining Antimalarial Activity
    Pharmaceutical Research, 1993
    Co-Authors: John K. Baker
    Abstract:

    In simulated stomach acid (aqueous 0.01 M HC1, 37°C) β-Arteether decomposed (half-life, 441 ± 17 min) to dihydroartemisinin, which subsequently rearranged to a new compound (1) having an endoperoxide group and an aldehyde group. The in vitro antimalarial activity of dihydroartemisinin is similar to that of β-Arteether, whereas compound 1 had approximately 1/10th the activity of β-Arteether. Compound 1 was prepared in sufficient quantities to afford samples for biological evaluation and a complete chemical characterization with 1H- and 13C-NMR and mass spectrometry. While β-Arteether would be somewhat unstable in the stomach, if the drug were administered on an empty stomach (emptying time, ≈30 min) as a suspension or tablet, sufficient quantities of intact Arteether may reach the small intestines, where it would be stable and readily absorbed. Its decomposition products, dihydroartemisinin and 1, may also contribute to the antimalarial activity of the administered drug following oral administration.

Georgette Guemkam - One of the best experts on this subject based on the ideXlab platform.

  • CLINICAL TRIAL OF -Arteether VERSUS QUININE FOR THE TREATMENT OF CEREBRAL MALARIA IN CHILDREN IN YAOUNDE, CAMEROON
    2015
    Co-Authors: Roger Moyou-somo, Felix Tietche, Martin Ondoa, L E Kouemeni, Tetanye Ekoe, Elie Mbonda, Charles Nsangou, Bonaventure Jemea, Georgette Guemkam
    Abstract:

    Abstract. One hundred and two children aged 0–10 years with cerebral malaria (Blantyre coma score of 2 or less) were randomly treated either with intramuscular Arteether (3.2 mg/kg on Day 0, followed by 1.6 mg/kg on Days 1 to 4) or intravenous (IV) quinine dihydrochloride (20 mg of the salt/kg, followed by 10 mg of the salt/kg every 8 hr up to Day 6). Treatment with oral quinine sulfate (10 mg/kg every 8 hr) was substituted for IV quinine when the patient was able to take oral medicine. All patients were followed up in the hospital for 7 days; thereafter, they were treated as outpatients on Days 14, 21, and 28. Mortality rate, the main efficacy parameter, was 11.8 % lower in the Arteether treatment group than in the quinine group (15.7 % versus 27.4%); however, the difference was not significant (P 0.25). Means for fever clearance time, coma resolution time, and parasite clearance time were similar in the 2 treatment groups (42.2 34.9 hr; 34.8 18.8 hr, and 46.3 28.5 hr, respectively for Arteether, versus 45.0 26.7 hr; 30.3 18.9 hr, and 40.7 18.9 hr, respectively, for quinine). At 28 days, the cure rates were 73.2 % and 64.9 % for the Arteether and quinine treatment groups, respectively. Arteether is safe and therapeutically at least as effective as quinine for the treatment of cerebral malaria in children in Cameroon. Because of its ease of administration, Arteether appears to be suited for use in the rural zones where monitoring facilities do not exist

  • clinical trial of beta Arteether versus quinine for the treatment of cerebral malaria in children in yaounde cameroon
    American Journal of Tropical Medicine and Hygiene, 2001
    Co-Authors: Roger Moyousomo, Felix Tietche, Martin Ondoa, L E Kouemeni, Tetanye Ekoe, Elie Mbonda, Charles Nsangou, Bonaventure Jemea, Georgette Guemkam
    Abstract:

    One hundred and two children aged 0-10 years with cerebral malaria (Blantyre coma score of 2 or less) were randomly treated either with intramuscular Arteether (3.2 mg/kg on Day 0, followed by 1.6 mg/kg on Days 1 to 4) or intravenous (i.v.) quinine dihydrochloride (20 mg of the salt/kg, followed by 10 mg of the salt/kg every 8 hr up to Day 6). Treatment with oral quinine sulfate (10 mg/kg every 8 hr) was substituted for i.v. quinine when the patient was able to take oral medicine. All patients were followed up in the hospital for 7 days; thereafter, they were treated as outpatients on Days 14, 21, and 28. Mortality rate, the main efficacy parameter, was 11.8% lower in the Arteether treatment group than in the quinine group (15.7% versus 27.4%); however, the difference was not significant (P = 0.25). Means for fever clearance time, coma resolution time, and parasite clearance time were similar in the 2 treatment groups (42.2 +/- 34.9 hr; 34.8 +/- 18.8 hr, and 46.3 +/- 28.5 hr, respectively for Arteether, versus 45.0 +/- 26.7 hr; 30.3 +/- 18.9 hr, and 40.7 +/- 18.9 hr, respectively, for quinine). At 28 days, the cure rates were 73.2% and 64.9% for the Arteether and quinine treatment groups, respectively. Arteether is safe and therapeutically at least as effective as quinine for the treatment of cerebral malaria in children in Cameroon. Because of its ease of administration, Arteether appears to be suited for use in the rural zones where monitoring facilities do not exist.

Patrick B Memvanga - One of the best experts on this subject based on the ideXlab platform.

  • development of a liquid chromatographic method for the simultaneous quantification of curcumin β Arteether tetrahydrocurcumin and dihydroartemisinin application to lipid based formulations
    Journal of Pharmaceutical and Biomedical Analysis, 2014
    Co-Authors: Patrick B Memvanga, Veronique Preat, Jeremie Kindenge Mbinze, Eric Rozet, Philippe Hubert, R D Marini
    Abstract:

    A liquid chromatographic method was developed for the simultaneous separation of curcumin, β-Arteether, tetrahydrocurcumin and dihydroartemisinin based on the design of experiments and the design space methodology. The influence of the percentage of organic modifier, flow rate of the mobile phase and column temperature on the analytes separation was investigated. The optimal chromatographic separation was achieved on a C18 column (125mm×4mm, 5μm) using an isocratic elution with a mobile phase consisting of methanol-ammonium acetate (pH 4; 10mM) (80:20, v/v) at a flow rate of 0.45ml/min and a column temperature of 32.5°C. This method was then validated for simultaneous quantification of curcumin and β-Arteether contained in lipid-based formulations taking into account the β-expectation tolerance interval for the total error measurement. Finally, the suitability of the proposed liquid chromatographic method for routine analysis of curcumin and β-Arteether loaded in lipid-based formulations has been proven.

  • formulation design and in vivo antimalarial evaluation of lipid based drug delivery systems for oral delivery of β Arteether
    European Journal of Pharmaceutics and Biopharmaceutics, 2012
    Co-Authors: Patrick B Memvanga, Veronique Preat
    Abstract:

    β-Arteether, an effective artemisinin derivative, is used in the treatment of malaria but available only as an intramuscular injection. The objective of this work was to develop lipid-based formulations for oral administration of β-Arteether. Self-emulsifying drug delivery systems (SEDDSs) of low cost and with accessible excipients (groundnut or sesame oil, Maisine 35-1, Tween 80 or Cremophor EL, and absolute ethanol) were formulated. In 250 ml of simulated gastric medium, 1g of these SEDDS solubilized the daily dose of β-Arteether and formed lipid droplets of average size 80-250 nm. No toxicity against Caco-2 intestinal cells was observed. Using a mouse model, the efficacy of these Arteether lipid formulations against Plasmodium berghei was evaluated. A daily dose of 24 mg/kg for 4 days led to complete cure for more than 45 days in 100% of treated mice and had an antimalarial efficacy comparable to that of an intramuscular oily solution of Arteether and significantly higher than that of an oily solution of β-Arteether given orally at the same dose. In conclusion, lipid-based drug delivery systems constitute a promising approach for the oral administration of β-Arteether.

Marini Djang'eing'a Roland - One of the best experts on this subject based on the ideXlab platform.

  • Simple LC Isocratic Methods Development, Validation, and Application in the Analysis of Poor Quality Antimalarial Medicines
    'Scientific Research Publishing Inc.', 2017
    Co-Authors: Habyalimana Védaste, Mbinze Kindenge Jéremie, Yemoa Loconon Achille, Kadima Ntokamunda Justin-léonard, Hubert Philippe, Marini Djang'eing'a Roland
    Abstract:

    peer reviewedaudience: researcher, professional, student, popularizationLiquid chromatographic methods in isocratic mode for the analysis of poor quality medicines are privileged due to their simplicity and facility in methods development. They are generally fast; do not need to be re-equilibrated between sample injections; have larger flexibility with acceptable changes on different column dimensions; and are applicable to LC systems equipped with simple or high developed pumps. In this study, we focused on developing simple isocratic methods using classical mobile phase composed by methanol and ammonium formate buffer for the analysis of most common antimalarial medicines marketed in malaria endemic countries and susceptible of being counterfeit/falsified, substandard and degraded. The selected medicines were quinine and related cinchona alkaloids in tablets and injectable forms; artemether/ lumefantrine tablets; and artemisinin compounds (Arteether, artemether, and artesunate) in injectable forms. The current methods were developed thanks to simple methodological approach consisting in sequential isocratic runs through adjustment or adaptation of existing methods to obtain optimal analytical conditions without complex design of experiments that might be long and costly. Then, the new methods presented shorter analysis time; allowed increase of sample analysis throughput; and obviously consumed little mobile phase solvents on classical analytical columns: 50 - 250 mm of length (L), 4.6 mm of internal diameter (I.D.), and 3.5 - 5.0 μm of particle size (dp)

  • Simple LC Isocratic Methods Development, Validation, and Application in the Analysis of Poor Quality Antimalarial Medicines
    2017
    Co-Authors: Habyalimana Védaste, Mbinze Kindenge Jéremie, Yemoa Loconon Achille, Kadima Ntokamunda Justin-léonard, Hubert Philippe, Marini Djang'eing'a Roland
    Abstract:

    Liquid chromatographic methods in isocratic mode for the analysis of poor quality medicines are privileged due to their simplicity and facility in methods development. They are generally fast; do not need to be re-equilibrated between sample injections; have larger flexibility with acceptable changes on different column dimensions; and are applicable to LC systems equipped with simple or high developed pumps. In this study, we focused on developing simple isocratic methods using classical mobile phase composed by methanol and ammonium formate buffer for the analysis of most common antimalarial medicines marketed in malaria endemic countries and susceptible of being counterfeit/falsified, substandard and degraded. The selected medicines were quinine and related cinchona alkaloids in tablets and injectable forms; artemether/ lumefantrine tablets; and artemisinin compounds (Arteether, artemether, and artesunate) in injectable forms. The current methods were developed thanks to simple methodological approach consisting in sequential isocratic runs through adjustment or adaptation of existing methods to obtain optimal analytical conditions without complex design of experiments that might be long and costly. Then, the new methods presented shorter analysis time; allowed increase of sample analysis throughput; and obviously consumed little mobile phase solvents on classical analytical columns: 50 - 250 mm of length (L), 4.6 mm of internal diameter (I.D.), and 3.5 - 5.0 μm of particle size (dp).Peer reviewe

  • Development of a liquid chromatographic method for thesimultaneous quantification of curcumin, -Arteether,tetrahydrocurcumin and dihydroartemisinin. Application to lipid-based formulations
    'Elsevier BV', 2014
    Co-Authors: Memvanga Bondo Patrick, Mbinze Kindenge Jéremie, Hubert Philippe, Rozet Eric, Préat Véronique, Marini Djang'eing'a Roland
    Abstract:

    A liquid chromatographic method was developed for the simultaneous separation of curcumin, B-Arteether, tetrahydrocurcumin and dihydroartemisinin based on the design of experiments and the design space methodology. The influence of the percentage of organic modifier, flow rate of the mobile phase and column temperature on the analytes separation was investigated. The optimal chromatographic separation was achieved on a C18 column (125 mm × 4 mm, 5 µm) using an isocratic elution with a mobile phase consisting of methanol:ammonium acetate (pH 4; 10 mM) (80/20, v/v) at a flow rate of 0.45 ml/min and a column temperature of 32.5◦C. This method was then validated for simultaneous quantification of curcumin and B -Arteether contained in lipid-based formulations taking into account the B -expectation tolerance interval for the total error measurement. Finally, the suitability of the proposed liquid chromatographic method for routine analysis of curcumin and B -Arteether loaded in lipid-based formulations has been proven.Peer reviewe

  • Development of a liquid chromatographic method for thesimultaneous quantification of curcumin, -Arteether,tetrahydrocurcumin and dihydroartemisinin. Application to lipid-based formulations
    'Elsevier BV', 2014
    Co-Authors: Memvanga Bondo Patrick, Mbinze Kindenge Jéremie, Hubert Philippe, Rozet Eric, Préat Véronique, Marini Djang'eing'a Roland
    Abstract:

    peer reviewedaudience: researcher, professional, student, popularizationA liquid chromatographic method was developed for the simultaneous separation of curcumin, B-Arteether, tetrahydrocurcumin and dihydroartemisinin based on the design of experiments and the design space methodology. The influence of the percentage of organic modifier, flow rate of the mobile phase and column temperature on the analytes separation was investigated. The optimal chromatographic separation was achieved on a C18 column (125 mm × 4 mm, 5 µm) using an isocratic elution with a mobile phase consisting of methanol:ammonium acetate (pH 4; 10 mM) (80/20, v/v) at a flow rate of 0.45 ml/min and a column temperature of 32.5◦C. This method was then validated for simultaneous quantification of curcumin and B -Arteether contained in lipid-based formulations taking into account the B -expectation tolerance interval for the total error measurement. Finally, the suitability of the proposed liquid chromatographic method for routine analysis of curcumin and B -Arteether loaded in lipid-based formulations has been proven.Projet PIC-CU

Julie A Simpson - One of the best experts on this subject based on the ideXlab platform.

  • Clinical and neuro-physiological study of the effects of multiple doses of artemisinin on brain stem function in Vietnamese patients
    2015
    Co-Authors: E Kissinger, Tran Tinh Hien, Nguyen Thanh Hung, Nguyen Dang Nam, N L Tuyen, B V Dinh, C Mann, Nguyen Hoan Phu, Pham Phu Loc, Julie A Simpson
    Abstract:

    Abstract. The qinghaosu (artemisinin) group of drugs is the most important new class of antimalarials developed in the last fifty years. Although there has been no clinical evidence of neurotoxicity, an unusual pattern of damage to specific brain-stem nuclei has been reported in experimental animals receiving high doses of Arteether or artemether. Detailed clinical examinations, audiometry, and brain stem auditory evoked potentials (BSAEPs) were assessed in 242 Vietnamese subjects who had previously received up to 21 antimalarial treatment courses of artemisinin or artesunate alone and 108 controls from the same location who had not received these drugs. There was no evidence of a drug effect on the clinical or neurophysiological parameters assessed. In this population there was no clinical or neurophysiological evidence of brain-stem toxicity that could be attributed to exposure to artemisinin or artesunate

  • clinical and neurophysiological study of the effects of multiple doses of artemisinin on brain stem function in vietnamese patients
    American Journal of Tropical Medicine and Hygiene, 2000
    Co-Authors: E Kissinger, Tran Tinh Hien, Nguyen Thanh Hung, Nguyen Dang Nam, N L Tuyen, B V Dinh, C Mann, Nguyen Hoan Phu, Pham Phu Loc, Julie A Simpson
    Abstract:

    The qinghaosu (artemisinin) group of drugs is the most important new class of antimalarials developed in the last fifty years. Although there has been no clinical evidence of neurotoxicity, an unusual pattern of damage to specific brain-stem nuclei has been reported in experimental animals receiving high doses of Arteether or artemether. Detailed clinical examinations, audiometry, and brain stem auditory evoked potentials (BSAEPs) were assessed in 242 Vietnamese subjects who had previously received up to 21 antimalarial treatment courses of artemisinin or artesunate alone and 108 controls from the same location who had not received these drugs. There was no evidence of a drug effect on the clinical or neurophysiological parameters assessed. In this population there was no clinical or neurophysiological evidence of brain-stem toxicity that could be attributed to exposure to artemisinin or artesunate.